Method for treating septic shock

ABSTRACT

Levosimendan, or (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, which has been mentioned for the treatment of congestive heart failure, is useful in the treatment of septic shock.

This application is a national stage filing of PCT InternationalApplication No. PCT/FI01/00614, filed on Jun. 28, 2001. This applicationalso claims the benefit of priority under 35 U.S.C. § 119(a) to Finnishpatent application no. 20001542, filed on Jun. 29, 2000.

TECHNICAL FIELD

The present invention relates to a method for the treatment of septicshock by administering levosimendan, or(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I), or pharmaceutically acceptable salts thereof, to a patient in needof such treatment.

BACKGROUND OF THE INVENTION

Levosimendan, which is the (−)-enantiomer of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,and the method for its preparation is described in EP 565546 B1.Levosimendan is potent in the treatment of heart failure and hassignificant calcium dependent binding to troponin. Levosimendan isrepresented by the formula:

The hemodynamic effects of levosimendan in man are described inSundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066 and inLilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69,1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosingis described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol.,26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment ofmyocardial ischemia is described in WO 93/21921. The use of levosimendanin the treatment of pulmonary hypertension is described in WO 99/66912.Clinical studies have confirmed the beneficial effects of levosimendanin heart failure patients.

Septic shock (also known as sepsis) is the leading cause of morbidityand mortality in the intensive care units. Despite increased knowledgeabout the pathophysiology underlying the clinical symptoms mortalityremains high and has not decreased substantially over the last decades.

There are several causes of septic shock including bacterial, fungal andviral infections as well as non-invasive stimuli such as multipletrauma, severe burns, organ transplantations and pancreatitis. The fataloutcome of septic shock has recently been linked to the systemic releaseof substantial amounts of various cytokines in the body.

Septic shock requires prompt treatment since the patient's conditionoften deteriorates rapidly. Symptoms of septic shock include fever,hypothermia, falling blood pressure, rapid breathing, rapid heartbeat,skin lesions and leakage of plasma proteins into the tissues, metabolicacidosis and elevated plasma lactate. Septic shock is particularlycharacterised by maldistribution of blood flow and disturbances intissue oxygen in various organs of the body. Distribution of blood flowmay become heterogenous with subsequent under- and overperfusion ofvarious tissues. These disturbances have been noted both at the macro-as well as at the microcirculatory level. Septic patient usually die asa result of poor tissue perfusion and injury followed by multiple organfailure.

One of the organs in which the disturbances in nutritive flow isespecially important is the gut. The importance of preserved ofsplanchnic blood flow in various shock conditions, including septicshock, has been largely emphasized in the literature. Reductions insplanchnic blood flow have been a suggested contributor to thedevelopment of multiple organ failure as well as maintenance of sepsisby translocation of gut derived bacteria over a hyperpermeable gut wall.

Current therapeutic strategies in sepsis include antibiotics, in certaincases surgical intervention, blood volume replacement as well asinotropic support to the failing circulation. However, the currenttherapy has not proven to be successful. Insufficient response tointropic drugs in terms of cardiac output is not uncommon. Also thedistribution of blood flow to various organs may become negativelyaffected. For example, splanchnic blood flow is not increased in spiteof increased cardiac output. Thus, an improved method for treatingseptic shock would be of great value.

SUMMARY OF THE INVENTION

It has now been found that in the porcine model of endotoxin shocklevosimendan unexpectedly counteracts endotoxin-induced splanchnichyperperfusion as well as endotoxin-induced decreases in cardiac output.These favourable effects suggest that levosimendan is particularlybeneficial in the treatment of septic shock.

Therefore, the present invention provides the use of(−)-[[4-(1,4,5,6-tetra-hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileor a pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment septic shock.

The present invention also provides a method for the treatment of septicshock in a patient, said method comprising administering to a patient inneed thereof an effective amount of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrileor a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of levosimendan on the cardiac index in aporcine model of endotoxin shock compared to control.

FIG. 2 shows the effect of levosimendan on the portal blood flow indexin a porcine model of endotoxin shock compared to control.

FIG. 3 shows the effect of levosimendan on the pulmonary vascularresistance index in a porcine model of endotoxin shock compared tocontrol.

FIG. 4 shows the effect of levosimendan on the portal venous blood flowlactate in a porcine model of endotoxin shock compared to control.

DETAILED DESCRIPTION

The method of the invention comprises a step of administering to asubject an amount of levosimendan effective to reduce, inhibit orprevent symptoms of septic shock in a patient. In particular the methodcomprises administering to a patient an amount of levosimendan effectiveto counteract endotoxin-induced harmful effects on the peripheralcirculation of a patient. The term “treatment of septic shock” isintended to cover therapeutic and/or prophylactic treatments. Theadministration of levosimendan can be enteral, e.g. oral or rectal, orparenteral, e.g. intravenous or transdermal.

The effective amount of levosimendan to be administered to a subjectdepends upon the condition to be treated, the route of administration,age, weight and the condition of the patient. In general levosimendan isadministered orally to man in daily dose from about 0.1 to 20 mg,preferably from 0.2 to 15 mg, more preferably from 0.5 to 10 mg, givenonce a day or divided into several doses a day, depending on the age,body weight and condition of the patient. Levosimendan can beadministered by intravenous infusion using the infusion rate typicallyfrom about 0.01 to 10 μg/kg/min, more typically from about 0.02 to 5μg/kg/min. For the intravenous treatment of septic shock an intravenousbolus of 10-200 μg/kg followed by infusion of 0.2-3 μg/kg/min may beneeded.

Levosimendan is formulated into dosage forms suitable for the treatmentof septic shock using the principles known in the art. It is given to apatient as such or preferably in combination with suitablepharmaceutical excipients in the form of tablets, dragees, capsules,suppositories, emulsions, suspensions or solutions whereby the contentsof the active compound in the formulation is from about 0.5 to 100% perweight. Choosing suitable ingredients for the composition is a routinefor those of ordinary skill in the art. It is evident that suitablecarriers, solvents, gel forming ingredients, dispersion formingingredients, antioxidants, colours, sweeteners, wetting compounds,release controlling components and other ingredients normally used inthis field of technology may be also used.

For oral administration in tablet form, suitable carriers and excipientsinclude e.g. lactose, corn starch, magnesium stearate, calcium phosphateand talc. For oral administration in capsule form, useful carriers andexcipients include e.g. lactose, corn starch, magnesium stearate andtalc. For controlled release oral compositions release controllingcomponents can be used. Typical release controlling components includehydrophilic gel forming polymers such as hydroxypropylmethyl cellulose,hydroxypropyl cellulose, carboxymethyl celluloses, alginic acid or amixture thereof; vegetable fats and oils including vegetable solid oilssuch as hydrogenated soybean oil, hardened castor oil or castor seed oil(sold under trade name Cutina HR), cotton seed oil (sold under the tradenames Sterotex or Lubritab) or a mixture thereof; fatty acid esters suchas triglycerides of saturated fatty acids or their mixtures e.g.glyceryl tristearates, glyceryl tripalmitates, glyceryl trimyristates,glyceryl tribehenates (sold under the trade name Compritol) and glycerylpalmitostearic acid ester.

Tablets can be prepared by mixing the active ingredient with thecarriers and excipients and compressing the powdery mixture intotablets. Capsules can be prepared by mixing the active ingredient withthe carriers and excipients and placing the powdery mixture in capsules,e.g. hard gelatin capsules. Typically a tablet or a capsule comprisesfrom about 0.1 to 10 mg, more typically 0.2 to 5 mg, of levosimendan.

Formulations suitable for intravenous administration such as injectionor infusion formulation, comprise sterile isotonic solutions oflevosimendan and vehicle, preferably aqueous solutions. Typically anintravenous infusion solution comprises from about 0.01 to 0.1 mg/ml oflevosimendan.

Salts of levosimendan may be prepared by known methods. Pharmaceuticallyacceptable salts are useful as active medicaments, however, preferredsalts are the salts with alkali or alkaline earth metals.

EXAMPLES Pharmaceutical Example

Hard gelatin capsule size 3 Levosimendan  2.0 mg Lactose  198 mg

The pharmaceutical preparation in the form of a capsule was prepared bymixing levosimendan with lactose and placing the powdery mixture in hardgelatin capsule.

Experiments

20 kg landrace pigs were anesthetized and catheterized. After baselinemeasurements 8 pigs received 200 μg/kg levosimendan as a 10 minute bolusfollowed by an infusion of 200 μg/kg/hour. 9 animals served as controls.

In the second phase of the experiment the animals were given an infusionof endotoxin (from E. Coli bacteria) 30 minutes after the start of thebolus dose of levosimendan. The endotoxin infusion was maintained for 3hours and the levosimendan infusion was maintained throughout theexperiment until 5 hours after onset of endoxemia. Comparison betweenthe two groups was made with ANOVA.

The changes in the cardiac index, splanchnic (portal) blood flow index,portal venous blood lactate and pulmonary vascular resistance are shownin FIGS. 1-4. In the Figures, (−0.5 h) means the start of levosimendanbolus and (0 h) the start of endotoxin infusion. The results show thatlevosimendan can significantly counteract endotoxin-induced circulatorydisorders. All levosimendan treated animals survived whereas one animalin the control group died.

1. A method for the treatment of septic shock in a patient, said methodcomprising administering to a patient in need thereof an effectiveamount of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrileor a pharmaceutically acceptable salt thereof.
 2. A method according toclaim 1, wherein an intravenous bolus of 10-200 μg/kg followed byinfusion of 0.2-3 μg/kg/min of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileis administered.
 3. A method according to claim 1, which comprisesadministering the(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile,or pharmaceutically acceptable salt thereof, in the form of a solution.4. A method according to claim 1, which comprises administering the(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile,or pharmaceutically acceptable salt thereof, in the form of anintravenous solution.
 5. A method according to claim 1, which comprisesadministering(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile.6. A method according to claim 1, which comprises administering apharmaceutically acceptable salt of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile.7. A method according to claim 6, wherein the salt is an alkali oralkaline earth metal salt.
 8. A method for increasing splanchnic bloodflow in a patient suffering from septic shock comprising administeringto a patient in need thereof an effective amount of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile,or a pharmaceutically acceptable salt thereof.